Statin modulation of immunotherapy for Alzheimer disease Summary/Abstract Alzheimer's disease (AD) is the most common dementing illness in the elderly and becoming major veteran's health and/or healthcare issues. It is pathologically characterized by the presence of extracellular senile plaques in the brain primarily composed of 40-42 amino acid length amyloid beta (A(1-40, 42) peptides. Strategies targeting the clearance of A( plaques or neutralization of the precursor soluble or oligomeric forms of A( which precede plaque formation have been the focus of intense research for patients suffering from AD. A different anti-AD strategy, vaccination with the A( peptide, also reduces A( deposition in AD transgenic mice and improves cognition. Two major hypotheses regarding the actions of A( immunotherapy are the facilitation of microglial phagocytosis via Fc receptors and promotion of A( removal from the brain by increasing the brain/blood concentration gradient via anti-A( antibody peripheral sink. Clinical trials of this therapy were halted because of brain inflammation in subset of cases. In spite of this side-effect, the first reports form this trial suggested some success in slowing the rate of dementia progression in patients generating antibodies against brain A(. Our long-term objective is to test the hypothesis that combined anti-A( therapy (vaccination) and lovastaitn (anti-CD40 therapy) will be mutually beneficial as a co-administrated AD immunotherapy strategy in not only abrogating inflammation that may result from vaccination, but also in improving memory deficits in AD model mice. Lovastatin is predicted to abrogate the potential adverse effects of the anti-A( immunotherapy by increasing anti-inflammatory cytokines in the brain, as well as by slowing the maturation of the microglia into the pro-inflammatory antigen presenting phenotype. In addition, lovastatin-mediated disruption of CD40 signaling should enhance the A( clearing properties of A( antibodies by polarizing activated microglia in a phagocytic state. These actions will be tested in vitro and in vivo in three specific aims designed to fully characterize lovastatin modulation of microglial phagocytic and antigen presenting phenotypes following CD40 ligation in terms of cell surface, cytokine, and signaling markers specific to phagocytic or antigen presenting states of microglia. Further the uptake of IgG-opsonized A( by primary microglia will be measured in the presence and absence of lovastatin. Additionally we will examine putative reductions in AD-like pathology following lovastatin treatment Tg2576 mice treated with both lovastatin and an agonist mouse CD40 antibody. Finally additive or synergistic therapeutic effects are expected to occur when lovastatin is co-administered with A( vaccine and this will be tested by comparing A( vaccinated and PBS immunized Tg2576 mice treated with lovastatin or control and sacrificed at several ages. PUBLIC HEALTH RELEVANCE: Project Narrative Alzheimer's disease (AD) is a chronic, progressive dementia associated with impairment in memory and behavior. It currently accounts for about 70% of all dementias and onset typically occurs in mid-late life. The frequency doubles every five years after age 60, increasing from a prevalence of about 1% in individuals aged 60 years to about 40% among those aged 85 years or greater. Thus this disease is a clear healthcare problem for both veterans and all individuals living past the age of 60. Furthermore, as the aging population grows, AD will become an even greater socioeconomic problem. Indeed AD prevalence is expected to rise dramatically through the mid 21st century, concurrently with various conflicts in the Middle East. It is projected the number of AD patients in the U.S.A. will rise to 13.2 million by that time, not accounting for U.S. forces deployed oversees. In terms of VA healthcare costs, it was estimated that the total direct and indirect costs related to AD alone are, on a per-patient basis, some $91,000 over the course the illness. The major brain abnormality in AD is thought is to be the presence of extracellular senile plaques in the brain primarily composed of amyloid beta (A() peptides. Strategies targeting the clearance of these plaques from the brain may help patients suffering from AD. We have experience with two such strategies in mouse models. One is vaccination with the A( peptide. We found this decreased senile plaques in AD mouse models while improving their memory. The second strategy is the administration of a common anti-cholesterol drug known as lovastatin. This too had similar effects as vaccination. However neither strategy alone is sufficient as recovery of the brain, and a return to normal behavior is not seen. Further, clinical trials of vaccination were halted due to serious side effects which we likely may be overcome by the addition of lovastatin. Thus, our long-term objective is to test the hypothesis that combined vaccination and lovastaitn therapy will be mutually beneficial as a co- administrated AD treatment in AD model mice. Lovastatin is predicted to abrogate the potential adverse effects of the A( vaccination by increasing anti-inflammatory chemicals in the brain and should also reduce memory problems further than vaccination alone. This will be tested by comparing behavior and brain health in several mouse groups including: A( vaccinated (alone) and those treated with lovastatin plus A( vaccination.